The impairment of pineal function with age results in insufficient secretion of the hormone melatonin from this gland. Thus, the administration of melatonin to the elderly has been considered as a treatment for the aging-associated loss of circadian rhythms. Or for neuroendocrine and immune imbalances. The lack of melatonin and its antioxidative activity in the elderly might be important in the pathophysiology of aging-associated neurodegenerative brain disorders. Melatonin may influence the receptors for the inhibitory neurotransmitter gamma aminobutyric acid (GABA); the expression of these receptors is affected by aging. We and others have shown that melatonin protects against neurotoxic effects of the excitatory neurotransmitter glutamate, in particular when kainate-sensitive glutamate receptors are stimulated. We found that administration of melatonin to rats attenuates kainate- induced brain damage, and that greater damage occurs after kainate in old adult animals. This damage is also greater in pinealectomized than in sham-operated rats. In addition, we found that pinealectomy decreases the expression of mRNA for the alpha1 subunit of the GABAA receptor complex. Others have reported a decreased expression of alpha1 receptor subunit mRNA in old rats. We hypothesize that the melatonin deficiency that occurs with aging is responsible for changes in the expression of GABAA receptor subunits, increased neurotoxic kainate excitotoxicity, and for a changed antiexcitotoxic efficacy of benzodiazepines (BZDs). We propose the following AIMs: AIM 1: testing the hypothesis that aging and pinealectomy (PIN-X) similarly potentiate kainate-triggered hippocampal damage, and that administration of exogenous melatonin is neuroprotective both in old and PIN-X rats; AIM 2: testing the hypothesis that aging and PIN-X similarly affect the content of GABA receptor subunits mRNAs in the rat brain and that the effect of PIN-X can be reversed by melatonin; AIM 3: Testing the hypothesis that the anticonvulsive/neuroprotective action of BZDs against kainate is similarly affected by aging and pinalectory. The project proposed is a logical extension of our previous work into the area of aging. The results we will obtain might help to direct treatment strategies for neurodegenerative diseases associated with aging toward the aging component of these disorders, rather than at disease-specific mechanisms.